Obesity, which is an excess of body fat relative to lean body mass, is a chronic disease that is highly prevalent in modern society. It is associated with decreased life span and numerous medical problems, including adverse psychological development, coronary artery disease, hypertension, stroke, Type 2 diabetes, hyperlipidemia, and some cancers. A hallmark characteristic of obesity is an increase in white adipose tissue (WAT) mass that is largely due to accumulation of triacylglycerol. This increase in WAT mass is a key contributor to obesity-associated complications.
Diacylglycerol O-acyltransferase 1 (DGAT-1) is a membrane-bound enzyme that catalyzes the terminal step of triacylglycerol biosynthesis. DGAT-1 is expressed in the intestine and adipose tissue It has been found that DGAT-1 null mice do not become obese when challenged with a high fat diet in contrast to wild-type littermates (Smith, et al., Nature Genetics 25:87 90, 2000). DGAT-1 null mice display reduced postprandial plasma glucose levels and exhibit increased energy expenditure, but have normal levels of serum triglycerides.
The phenotype of the DGAT-1 null mouse, along with the results of our studies with DGAT-1 inhibitors in diet-induced obese (DIO) mice, indicate that such mice are resistant to diet induced obesity and have increased insulin and leptin sensitivity. These effects suggest that inhibition of DGAT in vivo may be a novel therapeutic target not only for obesity but also for diabetes. (Subauste A, Burant C F, Curr Drug Targets Immune Endocr Metabol Disord. 2003 December; 3(4):263-70.)
Therefore, a need exits in the art, however, for DGAT-1 inhibitors that have efficacy for the treatment of metabolic disorders such as, for example, obesity, Type 2 diabetes and insulin resistance syndrome. Further, a need exists in the art for DGAT-1 inhibitors having IC50 values of less than about 1000 nM and preferably below 100 nM.